Palmoplantar Keratoderma, Mutilating, With Periorificial Keratotic Plaques

A number sign (#) is used with this entry because of evidence that Olmsted syndrome (OLMS), also known as mutilating palmoplantar keratoderma with periorificial keratotic plaques, is caused by heterozygous mutation in the TRPV3 gene (607066) on chromosome 17p13.

Description

Olmsted syndrome is a rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques with severe pruritus of lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas (summary by Lin et al., 2012). The digital constriction ('pseudoainhum') may progress to autoamputation of fingers and toes (Olmsted, 1927).

Clinical Features

Olmsted (1927) reported an Italian American boy who had onset of disease at age 18 months and, at 5 years, had symmetric massive yellow-gray horny plaques on his palms, divided into a mosaic pattern by several deep fissures. The lesions ended abruptly at the wrists and sides of the hands in a narrow red marginal zone. The plaques on the palmar surfaces of the fingers and thumbs were divided by transverse fissures at the interphalangeal joints, and there was flexion deformity of all digits that severely limited movement of the fingers. The nonhyperkeratotic skin of the dorsum of the fingers was purple-pink and almost cyanotic in appearance, and was frequently studded with tiny droplets of perspiration. There was pronounced subungual and circumungual hyperkeratosis, and the fingernails curved laterally and anteroposteriorly, forming a cap to each digit. The nail substance was thickened and lusterless, with transverse ridges. The plantar lesions resembled those of the palms, except for being somewhat less marked in degree, and there were similar nail changes. Hyperhidrosis of the hands and feet was variable. The facial lesions consisted of a row of yellow-brown plaques of epidermis, interrupted by fissures, situated parallel to the mucocutaneous junction of the lower lip and angles of the mouth. The anal fissure was filled completely by opposing plaques of rough red-brown epidermis, with a cone-shaped crater in the center; proctoscopic examination revealed no abnormalities of the anal canal or rectum. A biopsy of the anal lesion showed simple hyperkeratosis. The remainder of the skin appeared normal, and hair and teeth appeared uninvolved. Over 9 months of follow-up, the only successful treatment was prolonged soaking of involved parts in warm water followed by mechanical removal of the thickened epidermis; the lesions recurred within a few weeks of cessation of treatment. During the third month of observation, some of the transverse fissures at the interphalangeal joints became deeper, ultimately resulting in spontaneous amputation of 2 of the terminal phalanges. There was no family history of cutaneous disorders. Olmsted (1927) stated that associated hyperkeratotic lesions of the circumoral and circumanal regions had not previously been reported in congenital palmoplantar keratoderma.

Keir (1967) described an 11-year-old Jordanian girl who at 4 years of age developed plantar erythema, followed by scaling and the development of gross hyperkeratosis; at 7 years of age, her palms became similarly affected. Eventually the left and later the right fifth toes underwent spontaneous amputation. Examination at 11 years of age revealed severe, symmetric, sharply delineated palmar and plantar hyperkeratosis, contracting the hands and feet to such a degree as to render them useless. She had excessive sweating, most marked over the limbs, where it also seemed to penetrate the sodden horny material on the palms and soles. Fingernails and toenails were dystrophic, and there was mild ichthyosis of the scalp, arms, and trunk. Radiographs showed some resorption of all the terminal phalanges, with absence of the left fifth toe and almost total resorption of the right fifth toe. Histologic examination of the palmoplantar lesions showed a very thick horny layer with parakeratosis extending to the surface and considerable acanthosis; the granular layer was absent.

Atherton et al. (1990) described a 4-year-old boy, son of the Jordanian patient reported by Keir (1967), who developed keratoderma of his soles at 16 months of age, with appearance of palmar lesions at 23 months. All of his nails were thickened and transversally ridged. In addition to the palmoplantar lesions, the boy had a brownish-yellow crusted plaque about 2 cm wide, running below the entire length of the lower lip and including the angles of the mouth, but sparing the vermilion. The plaque had an erythematous border and closely resembled the palmoplantar skin changes. A similar lesion ran just below the nose, but there was no perianal involvement. The mother, who was now 32 years of age, had less severe PPK but had undergone the loss of 6 toes and had significant disability.

Poulin et al. (1984) described what they stated was the third case of Olmsted syndrome, citing Olmsted (1927) and Costa (1962). The patient was originally studied by Wells and Winkelmann (1961) and thought to represent a case of acrodermatitis enteropathica (201100) due to prominent periorificial dermatitis and alopecia, but the lesions did not respond to oral zinc therapy and the patient had a normal serum level of zinc. The 23-year-old male patient had severe diffuse, progressive, and transgrediens palmoplantar keratoderma with starfish-like extensions over the flexor surfaces of the wrists, periorificial keratoderma, linear keratoses on the flexor surfaces of the extremities and at sites of friction such as the axillae and the waist, keratosis pilaris (604093)-like lesions on the lateral aspect of the arms, leukokeratosis of the tongue, abnormalities of cutaneous adnexae with congenital alopecia universalis, onychodystrophy, and anhidrosis of the palms and soles with normal sweating elsewhere. The patient was also noted to have a missing premolar tooth; several other family members were reported to have multiple missing secondary teeth. His uninvolved skin was somewhat hyperelastic, and the large joints of the arms and legs showed striking laxity; a deceased uncle who had similar loose skin and joints was considered to have had Ehlers-Danlos syndrome type III (130020). Radiographs of the hands and feet showed generalized osteoporosis with pronounced atresia of the distal phalanges of all fingers and toes. Biopsy of the tongue lesion showed a dense infiltrate of lymphocytes, histiocytes, and plasma cells in the submucosa, with epithelial hyperplasia and parakeratosis, but no atypia of the epidermal cells.

Rivers et al. (1985) reported 4 affected individuals, spanning 3 generations of a family segregating mutilating PPK. The most severely affected was a 12-year-old boy, whose father, paternal aunt, and paternal grandmother were also affected. All had involvement of the palms and soles with contractures of the digits; the paternal aunt also had persistent fissuring at the stomal angles of her mouth and the boy had a reddened, dry area of the gluteal cleft. Histologic findings of the palmoplantar lesions were similar in all patients, showing marked hyperkeratosis, with a poor granular layer in areas of focal parakeratosis; the epidermis showed only mild acanthosis, and the dermis showed a sparse, primarily perivascular, lymphatic infiltrate. All of the patients responded to etretinate, with disappearance of the lesions of the palms and soles, and resolution of pseudoainhums after only 8 weeks of therapy; however, the perioral and sacral hyperkeratoses remained unchanged. All patients experienced a recurrence of palmoplantar discomfort within 2 weeks of withdrawal of etretinate, and therefore all were started on maintenance therapy.

Mevorah et al. (2005) reported a 2-year-old Arab girl from Gaza with mutilating PPK as well as periorificial hyperkeratosis involving the mouth, ear meatus, nostrils, and anus. The nails were dystrophic with subungual hyperkeratosis, and hair was sparse anteriorly. Teeth were normal, but there was leukokeratosis of the tongue and buccal mucosa. Ophthalmologic examination revealed a punctate corneal opacity of the left eye. Radiographs of hands and wrists were normal, including bone age, as was audiometric examination. Histopathology of palmar skin showed psoriasiform hyperplasia, hypogranulosis, and alternating parakeratosis, and orthohyperkeratosis. Electron microscopy demonstrated, in the malpighian layer, keratinocytes with well-developed desmosomes, increased intercellular spaces, finely distributed tonofilaments, and numerous glycogen granules, as well as a reduced number of keratohyaline granules. Of 100 scalp hairs examined from the sparse area, 14 showed pili torti or trichorrhexis nodosa-type defects, whereas no such defects were seen in 100 hairs from a normal area.

Lin et al. (2012) studied 5 sporadic Chinese patients with Olmsted syndrome, and 1 patient whose affected daughter died at 2 years of age. All affected individuals developed symptoms in the first year of life. The lesions were mild and limited in some patients, and in others extended to involve the neck, upper thorax, lower abdomen, inguinal folds, and upper inner thighs. Hair involvement varied, ranging from alopecia universalis with follicular papules to merely sparse curly hair. All patients complained of severe itching in the lesions, but thermosensation was normal in all, even in affected areas, and no additional neurologic or sensory anomalies were detected. Histopathology of keratotic skin lesions from 3 patients showed psoriasiform hyperplasia, orthohyperkeratosis, and parakeratosis with profound mast cell infiltration in the upper dermis.

Larregue et al. (2000) reported 2 unrelated boys with Olmsted syndrome. In a 7.5-year-old boy, born of consanguineous Algerian parents, the disorder began at 2 years of age and progressed to ainhum-like constrictions of the fingers and painful plantar lesions that impeded walking by 4 years of age; by 7 years of age, the child was confined to bed. On examination, he had a thick, yellow PPK studded with spiny keratotic projections and a macerated base. The border was well demarcated and less thick, with a very pruritic erythematous rim. His fingernails were rough, with a ground-glass appearance; his toenails were partially destroyed. The keratoderma was malodorous, and investigation revealed bacteriologic and mycologic infection. Severe growth retardation resulted in dwarfism with a delayed bone age of 4 years. Histologic examination of a palmar biopsy specimen showed a thickened epidermis overlaid by a thick, compact horny layer that was usually orthokeratotic but included vertical, well-demarcated stacks of parakeratosis. The granular cell layer was generally thickened, but was thin or absent at the level of parakeratosis. The stratum malpighii showed psoriasiform hyperplasia. Several mitoses were seen within the basal and occasional suprabasal keratinocytes, and the mitotic index (2.5%) was greater than that of a control specimen. A biopsy from the axillary region showed similar findings, with parakeratotic horny plugs within hair follicles. The second patient was a 9-year-old boy born to nonconsanguineous Spanish parents. At the age of 6 months he developed a scaly palmar erythema that progressed to a disabling PPK. At the age of 5 years ainhum-like constrictions and flexural contractures of the fingers developed; no amputation was seen. Clinical examination revealed a thick, fissured PPK with well-defined borders extending onto the heels. Perianal erythrokeratosis and intertrigo of the inguinal folds had been present since age 2 years, and perinasal and sublabial lesions were also seen. Growth was retarded and disability was moderate.

Clinical Variability

Duchatelet et al. (2014) reported a 5-year-old girl with superficial peeling of the skin of her toes at birth. After she started walking at 1 year of age, plantar keratoderma developed, initially only at the pressure points but gradually extending to most of the plantar surface. From at least 3 years of age, her plantar keratoderma associated with intense, acute flares of severe itching, burning pain, erythema, and warmth involving the hands, feet, and ears. The episodes were triggered by heat and associated with venous dilation, consistent with erythermalgia (see 133020). Because of extreme foot pain, the patient walked on hands and knees, resulting in mild palmar keratoderma, and used a wheelchair from age 3 years. Other features included increased sweating, thin brittle fingernails, and fine, dry, curly, and unmanageable hair. Microscopic examination of the hair showed superficial irregularities without specific abnormalities under polarizing microscopy. Skin biopsy demonstrated hyperplastic epidermis with hyperkeratosis, parakeratosis, hypergranulosis, and papillomatosis.

Reviews

Larregue et al. (2000) reviewed 20 cases of Olmsted syndrome consisting of 18 previously published and 2 new cases, unrelated boys, from their report. Examination of skin biopsies from 1 of the boys showed features suggesting that the disorder is related to epidermal hyperproliferation, including numerous centrioles by electron microscopy, increased mitotic count by histology, and increased numbers of silver-staining nucleolar organizer regions (AgNORs) on histochemical analysis. PPK was invariably present in the 20 patients and was always painful and disabling, with spontaneous autoamputations or ainhum-like constrictions of the fingers reported in 12 cases; additional patients had annular fissures of the base of the fingers. Associated nail dystrophy was almost invariably present. Erythematokeratotic scaly periorificial lesions were present in 19 cases and associated with intertriginous dermatosis in 12; Larregue et al. (2000) noted that the female patient who lacked periorificial and intertriginous lesions (Keir, 1967) gave birth to a boy with classic OLMS (Atherton et al., 1990). Onset of symptoms was at birth in 5 patients, with onset in the remainder of the cases at 2 weeks to 30 years of age. Keratosis follicularis was present in 5 patients and associated with diffuse alopecia in 2; 4 other patients had alopecia as well. Pruritus was a major symptom in 3 patients. In 13 of the 20 patients, the disorder was purely cutaneous. Other associations in the remaining 7 patients included growth retardation in 4 patients, 3 of whom were dwarfs. Laxity of major joints was noted in 3 patients and was severe in 2 of them, and corneal abnormalities were present in 2 patients. Although the original Olmsted patient (Olmsted, 1927) had psychomotor retardation, the 19 subsequently reported cases had normal IQs. Larregue et al. (2000) noted that OLMS may predispose to the development of cancers: 1 patient had 3 squamous cell carcinomas, occurring on the palm at 26 years of age, on the toe at age 38, and the dorsum of the hand at 39.5 years, respectively.

Mevorah et al. (2005) reviewed and tabulated the 32 published cases of Olmsted syndrome, noting that nonperiorificial keratotic lesions on different parts of the extremities (other than palms and soles) and in the intertriginous regions were frequently mentioned, with such lesions appearing as linear, streak-like hyperkeratoses and follicular keratosis-like keratotic papules. Eye lesions were observed in 22% of affected individuals, with severe corneal involvement in 2. High-tone hearing loss and congenital deaf-mutism had been reported, as well as joint laxity. Retarded physical development was present in 25% of patients, whereas mental retardation was mentioned twice. Recurrent bacterial and/or candidal infections, primarily in the keratotic areas, were common. Osteoporosis and/or osteolysis of the hands and feet occurred in some patients. Squamous cell carcinoma developed in the area of PPK in 2 cases. There was partial cutaneous expression of Olmsted syndrome in 2 families, in which some affected individuals did not exhibit periorificial involvement.

Inheritance

Atherton et al. (1990) reported a family in which there was clear transmission of Olmsted syndrome from mother to son, consistent with autosomal dominant inheritance.

Molecular Genetics

In a 9-year-old Chinese girl with Olmsted syndrome and her unaffected parents, Lin et al. (2012) performed genomewide whole-exome sequencing and identified a heterozygous missense mutation in the TRPV3 gene (G573S; 607066.0001) that was present in the patient but not her parents. Screening of the coding exons and flanking intron sequences in 5 additional Chinese patients with Olmsted syndrome revealed that 3 patients were heterozygous for the G573S mutation, 1 had a G573C mutation (607066.0002), and 1 had a W692G mutation (607066.0003). The mutations were confirmed to be de novo in the 5 patients for whom parental DNA was available, and none was found in 216 ethnically matched controls.

In a girl with Olmsted syndrome and erythermalgia, who was negative for mutation in the SCN9A gene (603415) and 4 pachyonychia congenita (see 167200)-associated keratin genes, Duchatelet et al. (2014) performed whole-exome sequencing and identified a de novo heterozygous missense mutation in the TRPV3 gene (L673F; 607066.0004). The mutation was not found in her parents or in 100 controls, 253 in-house exomes, or 6,503 individuals from the NHLBI Exome Sequencing Project. Duchatelet et al. (2014) acknowledged that the association of Olmsted syndrome and erythermalgia may have been coincidental in this patient; however, because the TRPV3 gene has been implicated in skin inflammation and nociceptive signaling, they suggested that the symptoms of erythermalgia could have been caused by the L673F mutation.

Exclusion Studies

In a 2-year-old Arab girl with Olmsted syndrome, Mevorah et al. (2005) sequenced the coding regions and exon-intron boundaries of genes previously implicated in the pathogenesis of mutilating palmoplantar keratodermas, including KRT1 (139350), GJB2 (121011), SLURP1 (606119), and LOR (152445), but did not detect any pathogenic sequence alteration.